Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers
Publication date
2016-07
Authors
Jansen, Anne M L
van Wezel, Tom
van den Akker, Brendy Ewm
Ventayol Garcia, Marina
Ruano, Dina
Tops, Carli Mj
Wagner, Anja
Letteboer, Tom G.W.
Gómez-García, Encarna B
Devilee, Peter
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Abstract
Many suspected Lynch Syndrome (sLS) patients who lack mismatch repair (MMR) germline gene variants and MLH1 or MSH2 hypermethylation are currently explained by somatic MMR gene variants or, occasionally, by germline POLE variants. To further investigate unexplained sLS patients, we analyzed leukocyte and tumor DNA of 62 sLS patients using gene panel sequencing including the POLE, POLD1 and MMR genes. Forty tumors showed either one, two or more somatic MMR variants predicted to affect function. Nine sLS tumors showed a likely ultramutated phenotype and were found to carry germline (n=2) or somatic variants (n=7) in the POLE/POLD1 exonuclease domain (EDM). Six of these POLE/POLD1-EDM mutated tumors also carried somatic MMR variants. Our findings suggest that faulty proofreading may result in loss of MMR and thereby in microsatellite instability.
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Jansen, A M, van Wezel, T, van den Akker, B E, Ventayol Garcia, M, Ruano, D, Tops, C M, Wagner, A, Letteboer, T G, Gómez-García, E B, Devilee, P, Wijnen, J T, Hes, F J & Morreau, H 2016, 'Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers', European Journal of Human Genetics, vol. 24, no. 7, pp. 1089-1092. https://doi.org/10.1038/ejhg.2015.252